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1.
Int Urogynecol J ; 35(2): 415-421, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38175280

ABSTRACT

INTRODUCTION AND HYPOTHESIS: Urinary incontinence (UI) is common in women and has a vast impact on quality of life (QOL), financial health, and work disability. Robust evidence demonstrates the efficacy of comprehensive conservative therapy (pelvic floor muscle training [PFMT], and behavioral and dietary modification) in the treatment of UI. However, numerous barriers impede access to this care, including limited specialized therapists, financial barriers, and scheduling obstacles. To address these barriers, we developed a novel comprehensive online pelvic floor program (oPFP). METHODS: We performed a prospective study assessing continence and QOL outcomes in women with stress urinary incontinence (SUI), urge urinary incontinence (UUI), or mixed urinary incontinence (MUI) treated with oPFP between May 2019 and November 2022. Outcomes were assessed at baseline and following completion of the 2-month program using the validated International Consultation on Incontinence Questionnaire-Female Lower Urinary Tract Symptoms, Urgency Perception Scale (UPS), Incontinence Impact Questionnaire (IIQ-7) questionnaires, and 24-h bladder diary. Data were analyzed using linear, Poisson mixed models, or generalized estimating equations. RESULTS: Twenty-eight women (2 SUI, 3 UUI, 23 MUI) were enrolled and 19 (2 SUI, 2 UUI, 15 MUI) completed the study. Following oPFP, participants showed significantly improved SUI domain scores (3.04 ± 0.19 vs 1.81 ± 0.23, p < 0.001), UPS reason score (2.52 ± 0.18 vs 2.05 ± 0.14, p = 0.003), IIQ-7 sum scores (5.16 ± 0.88 vs 3.07 ± 0.70, p = 0.038), and daily incontinence episodes (2.96 ± 0.60 vs 1.06 ± 0.29, p < 0.001). Mean patient-reported improvement was 5.4 ± 2.5 (ten-point Likert scale). Of respondents, 89% reported program satisfaction, ease of use, and would recommend the program to others. CONCLUSION: The oPFP results in significant improvements to a variety of UI and QOL measures. This program provides an important UI treatment option and gives women greater access to effective conservative therapy.


Subject(s)
Urinary Incontinence, Stress , Urinary Incontinence , Female , Humans , Pelvic Floor , Pilot Projects , Quality of Life , Prospective Studies , Urinary Incontinence/therapy , Urinary Incontinence, Urge/therapy , Urinary Incontinence, Stress/therapy
2.
Facial Plast Surg Aesthet Med ; 26(2): 219-227, 2024.
Article in English | MEDLINE | ID: mdl-38153410

ABSTRACT

Background: Hypoglossal-facial nerve (12-7) anastomosis can restore symmetry and voluntary movement on the face in patients with facial nerve paralysis. Traditional 12-7 transfer includes direct end-to-end nerve anastomosis, sacrificing the entire hypoglossal nerve. Contemporary, end-to-side anastomosis, or split anastomosis techniques limit tongue morbidity by preserving some hypoglossal nerve. Direct outcome comparisons between these techniques are limited. Objective: To compare reported outcomes of facial movement, tongue, speech, and swallow outcomes among the different types of hypoglossal-facial nerve anastomosis schemes. Evidence Review: For this systematic review and meta-analysis, a comprehensive strategy was designed to search PubMed, Scopus, and the Cochrane Database from inception to January 2021, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis, reporting guideline yielding 383 results. Any participant who underwent 12-7 transfer using any of the three techniques, with or without an interposition graft, and had documented preoperative and postoperative evaluation of facial nerve function with a validated instrument such as House-Brackmann (HB), was considered for inclusion. Secondary outcomes of synkinesis, tongue atrophy, and speech or swallowing dysfunction were also compared. Forty-nine studies met inclusion criteria, representing data from 961 total patients who underwent 12-7 transfer. Results: The proportion of good HB outcomes (HB I-III) did not differ by anastomosis type: End-to-side and end-to-end anastomosis (73% vs. 59%, p = 0.07), split and end-to-end anastomosis (62% vs. 59%, p = 0.88), and end-to-side anastomosis and split anastomosis (73% vs. 62%, p = 0.46). There was no difference in reported synkinesis rates between the anastomosis types. However, end-to-side anastomosis (z = 6.55, p < 0.01) and split anastomosis (z = 3.58, p < 0.01) developed less tongue atrophy than end-to-end anastomosis. End-to-side anastomosis had less speech/swallowing dysfunction than end-to-end anastomosis (z = 3.21, p < 0.01). Conclusion: End-to-side and split anastomoses result in similar HB facial nerve outcomes as the traditional end-to-end 12-7 anastomosis. End-to-side anastomosis has decreased complications of tongue atrophy and speech/swallow dysfunction compared to end-to-end anastomosis. In addition, split anastomosis has decreased rates of tongue atrophy compared to end-to-end anastomosis.


Subject(s)
Facial Paralysis , Synkinesis , Humans , Facial Nerve/surgery , Hypoglossal Nerve/surgery , Treatment Outcome , Atrophy/complications
3.
Heliyon ; 9(8): e19226, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37664715

ABSTRACT

A life-threatening manifestation of Covid-19 infection is a cytokine storm that requires hospitalization and supplemental oxygen. Various strategies to reduce inflammatory cytokines have had some success in limiting cytokine storm and improving survival. Agonists of adenosine A2A receptors (A2AR) reduce cytokine release from most immune cells. Apadenoson is a potent and selective anti-inflammatory adenosine analog that reduces inflammation. When administered by subcutaneous osmotic pumps to mice infected with SARS CoV-2, Apadenoson was found to improve the outcomes of infection as measured by a decrease in weight loss, improved clinical symptoms, reduced levels of proinflammatory cytokines and chemokines in bronchial lavage (BAL) fluid, and enhanced survival of K18-hACE2 transgenic mice. These results support further examination of A2AR agonists as therapies for treating cytokine storm due to COVID-19.

5.
J Alzheimers Dis ; 93(4): 1425-1441, 2023.
Article in English | MEDLINE | ID: mdl-37182881

ABSTRACT

BACKGROUND: In Alzheimer's disease (AD) brain, neuronal polarity and synaptic connectivity are compromised. A key structure for regulating polarity and functions of neurons is the axon initial segment (AIS), which segregates somatodendritic from axonal proteins and initiates action potentials. Toxic tau species, including extracellular oligomers (xcTauOs), spread tau pathology from neuron to neuron by a prion-like process, but few other cell biological effects of xcTauOs have been described. OBJECTIVE: Test the hypothesis that AIS structure is sensitive to xcTauOs. METHODS: Cultured wild type (WT) and tau knockout (KO) mouse cortical neurons were exposed to xcTauOs, and quantitative western blotting and immunofluorescence microscopy with anti-TRIM46 monitored effects on the AIS. The same methods were used to compare TRIM46 and two other resident AIS proteins in human hippocampal tissue obtained from AD and age-matched non-AD donors. RESULTS: Without affecting total TRIM46 levels, xcTauOs reduce the concentration of TRIM46 within the AIS and cause AIS shortening in cultured WT, but not TKO neurons. Lentiviral-driven tau expression in tau KO neurons rescues AIS length sensitivity to xcTauOs. In human AD hippocampus, the overall protein levels of multiple resident AIS proteins are unchanged compared to non-AD brain, but TRIM46 concentration within the AIS and AIS length are reduced in neurons containing neurofibrillary tangles. CONCLUSION: xcTauOs cause partial AIS damage in cultured neurons by a mechanism dependent on intracellular tau, thereby raising the possibility that the observed AIS reduction in AD neurons in vivo is caused by xcTauOs working in concert with endogenous neuronal tau.


Subject(s)
Alzheimer Disease , Axon Initial Segment , Mice , Animals , Humans , Axon Initial Segment/metabolism , Axon Initial Segment/pathology , Axons/pathology , Neurons/metabolism , Alzheimer Disease/pathology , Hippocampus/pathology , Mice, Knockout , tau Proteins/genetics , tau Proteins/metabolism
6.
Transl Androl Urol ; 12(12): 1775-1784, 2023 Dec 31.
Article in English | MEDLINE | ID: mdl-38196700

ABSTRACT

Background: Although pelvic floor muscle training (PFMT) is widely shown to improve post-prostatectomy incontinence (PPI), numerous barriers impede access to formal PFMT and include the limited availability of specialized therapists and financial or scheduling barriers. To address these barriers, we developed a novel online program delivering comprehensive long-term PFMT, pelvic floor education (PFE), and dietary/behavioral modification education. This study is a prospective interim analysis of online PFMT/PFE (oPFMT/PFE), with focus on feasibility, satisfaction, and continence outcomes. Methods: Patients anticipating robotic-assisted laparoscopic prostatectomy (RALP) were recruited (6/2021-9/2022) for oPFMT/PFE. oPFMT/PFE comprises a 12-month program of 3 phases, including multiple exercises with varied contraction types and duration, and comprehensive dietary and behavioral technique education. Incontinence and quality of life (QOL) outcomes are assessed at 3 weeks, 3, 6, and 12 months following RALP using validated International Consultation on Incontinence Questionnaire Male Lower Urinary Tract Symptoms (ICIQ-MLUTS) and Incontinence Impact Questionnaire (IIQ-7) questionnaires and additional items assessing satisfaction, improvement, and daily pad use. Primary study outcomes included ICIQ-MLUTS stress urinary incontinence (SUI) domain score (SDS) and SUI cure [ICIQ SUI domain score (SDS) =0]. Interim 6-month analysis was performed using mixed effects linear regression and mixed effects Poisson regression. Results: Analysis included 21 men (64±6 years). At 6-month follow-up, men undergoing oPFMT/PFE showed significant improvement in SDS compared to the 3-week time point [mean ± standard error (SE) =1.05±0.24 vs. 0.45±0.17, P=0.011], but still experienced higher scores than at baseline (P=0.017). Six-month patient-reported improvement averaged 7.42±0.74 (10-point Likert scale). All (100%) of 19 respondents (2 missing data) found the program easy to use, educational, and would recommend it to others, with 89% expressing satisfaction with the program. During patient interview at 6-month follow-up, no men reported inability to access the program online or any adverse events. Finally, IIQ-7 score improved significantly from the 3-week timepoint (4.47±1.10) at both time points (3-month 1.14±0.44, P<0.001 and 6-month 1.10±0.37, P<0.001), and neither 3- nor 6-month scores differed from baseline (P=0.808 and P=0.444, respectively). Conclusions: Our novel oPFMT/PFE yields significant improvements to validated urinary incontinence (UI) and QOL measures, providing a valuable and accessible treatment option for PPI.

7.
Plast Reconstr Surg ; 150(1): 105e-114e, 2022 07 01.
Article in English | MEDLINE | ID: mdl-35544320

ABSTRACT

BACKGROUND: Raynaud phenomenon, with and without scleroderma, is a common vasospastic condition that manifests with extremity pain and skin discoloration. When conservative management fails, complications such as ischemia, ulceration, and gangrene may warrant surgical intervention. The purpose of this study was to determine the risk factors and use of surgical intervention in this population. METHODS: A national insurance claims-based database with patient records from the Centers for Medicare and Medicaid Services was used for data collection. Patients with first diagnoses of Raynaud phenomenon, scleroderma, or both between 2005 and 2014 were identified. Primary outcomes included the presence of upper extremity amputation or vascular procedure, and history of amputation within 5 years of a vascular procedure. Secondary outcomes included hospital admissions, upper extremity wounds, and amputation within 1 year of diagnosis. RESULTS: The Raynaud phenomenon, scleroderma, and Raynaud phenomenon with scleroderma cohorts consisted of 161,300, 117,564, and 25,096 patients, respectively. A diagnosis of both Raynaud phenomenon and scleroderma increased the odds of upper extremity amputation by 5.4-fold, vascular procedure by 4.8-fold, and amputation within 5 years of a vascular procedure by 1.5-fold. Patients with Raynaud phenomenon or scleroderma alone were 3.1 and 5.6 times less likely to undergo amputation within 5 years of a vascular procedure, respectively. CONCLUSIONS: Patients with both Raynaud phenomenon and scleroderma have higher likelihoods of having upper extremity amputations, vascular procedures, and amputations following vascular procedures compared to each diagnosis alone. Vascular procedures are rarely being performed. Further research is necessary to establish a standard of care and determine whether early and more frequent intervention with vascular procedures can decrease amputation rates in this patient population. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.


Subject(s)
Raynaud Disease , Scleroderma, Localized , Aged , Amputation, Surgical/adverse effects , Humans , Ischemia/etiology , Medicare , Raynaud Disease/complications , Raynaud Disease/surgery , Retrospective Studies , Risk Factors , Treatment Outcome , United States
8.
Injury ; 53(9): 3059-3064, 2022 Sep.
Article in English | MEDLINE | ID: mdl-35623955

ABSTRACT

Trauma scoring systems were created to predict mortality and enhance triage capabilities. However, efficacy of scoring systems to predict mortality and accuracy of originally reported severity thresholds remains uncertain. A single-center, retrospective study was conducted at University of Virginia (UVA), an American College of Surgeons verified Level I trauma center. We compared four scoring systems: MGAP (Mechanism, Glasgow Coma Scale, Age, and arterial pressure), Injury Severity Score (ISS), New Injury Severity Score (NISS), and Trauma Related Injury Severity Score (TRISS) to predict in-hospital mortality and disposition from the emergency department to higher acuity level of care including mortality (i.e. operating room, intensive care unit, morgue) versus standard floor admission using area under the curve (AUC) for receiver operating characteristic analysis. Second, we examined sensitivity of these scores at standard thresholds to determine if adjustments were needed to minimize under-triage (sensitivity ≥95%). TRISS was the best predictor of mortality in a cohort of n = 16,265 with AUC of 0.920 (95% CI: 0.911-0.929, p<0.0001), followed by MGAP with AUC of 0.900 (95% CI: 0.889-0.911, p<0.0001), and finally ISS and NISS (0.830 (95% CI: 0.814-0.847) and 0.827 (95% CI: 0.809-0.844) respectively). NISS was the best predictor of high acuity disposition with an AUC of 0.729 (95% CI: 0.721-0.736, p<0.0001), followed by ISS with AUC of 0.714 (95% CI: 0.707-0.722, p<0.0001), and finally TRISS and MGAP (0.673 (95% CI: 0.665-0.682) and 0.613 (95% CI: 0.604-0.621) respectively (p<0.0001). At historic thresholds, no scoring system displayed adequate sensitivity to predict mortality, with values ranging from 73% for ISS to 80% for NISS. In conclusion, in the reported study cohort, TRISS was the best predictor of mortality while NISS was the best predictor of high acuity disposition. We also stress updating scoring system thresholds to achieve ideal sensitivity, and investigating how scoring systems derived to predict mortality perform when predicting indicators of morbidity such as disposition from the emergency department.


Subject(s)
Hospitals , Wounds and Injuries , Humans , Injury Severity Score , Predictive Value of Tests , ROC Curve , Retrospective Studies , Trauma Severity Indices , Wounds and Injuries/therapy
9.
PLoS Pathog ; 18(2): e1010324, 2022 02.
Article in English | MEDLINE | ID: mdl-35130324

ABSTRACT

The bacterial pathogen Shigella flexneri causes 270 million cases of bacillary dysentery worldwide every year, resulting in more than 200,000 deaths. S. flexneri pathogenic properties rely on its ability to invade epithelial cells and spread from cell to cell within the colonic epithelium. This dissemination process relies on actin-based motility in the cytosol of infected cells and formation of membrane protrusions that project into adjacent cells and resolve into double-membrane vacuoles (DMVs) from which the pathogen escapes, thereby achieving cell-to-cell spread. S. flexneri dissemination is facilitated by the type 3 secretion system (T3SS) through poorly understood mechanisms. Here, we show that the T3SS effector IpgD facilitates the resolution of membrane protrusions into DMVs during S. flexneri dissemination. The phosphatidylinositol 4-phosphatase activity of IpgD decreases PtdIns(4,5)P2 levels in membrane protrusions, thereby counteracting de novo cortical actin formation in protrusions, a process that restricts the resolution of protrusions into DMVs. Finally, using an infant rabbit model of shigellosis, we show that IpgD is required for efficient cell-to-cell spread in vivo and contributes to the severity of dysentery.


Subject(s)
Bacterial Proteins/metabolism , Cell Surface Extensions/metabolism , Phosphatidylinositol 4,5-Diphosphate/metabolism , Phosphoric Monoester Hydrolases/metabolism , Shigella flexneri/metabolism , Type III Secretion Systems/metabolism , Actins/metabolism , Animals , Bacterial Proteins/genetics , Cell Surface Extensions/microbiology , Colon/microbiology , Disease Models, Animal , Dysentery, Bacillary/microbiology , HT29 Cells , Host-Pathogen Interactions , Humans , Phosphoric Monoester Hydrolases/genetics , Rabbits , Shigella flexneri/genetics
10.
Chest ; 161(5): 1167-1179, 2022 05.
Article in English | MEDLINE | ID: mdl-34896356

ABSTRACT

BACKGROUND: During the COVID-19 pandemic, the University of Virginia adult cystic fibrosis (CF) center transitioned from in-person clinical encounters to a model that included interdisciplinary telemedicine. The pandemic presented an unprecedented opportunity to assess the impact of the interdisciplinary telemedicine model on clinical CF outcomes. RESEARCH QUESTION: What are the clinical outcomes of a care model that includes interdisciplinary telemedicine (IDC-TM) compared with in-person clinical care for patients with CF during the COVID-19 pandemic? STUDY DESIGN AND METHODS: Adults with CF were included. The prepandemic year was defined as March 17, 2019, through March 16, 2020, and the pandemic year (PY) was defined as March 17, 2020, through March 16, 2021. Patients were enrolled starting in the PY. Prepandemic data were gathered retrospectively. Telemedicine visits were defined as clinical encounters via secured video communication. Hybrid visits were in-person evaluations by physician, with in-clinic video communication by other team members. In-person visits were encounters with in-person providers only. All encounters included previsit screening. Outcomes were lung function, BMI, exacerbations, and antibiotic use. FEV1 percent predicted, exacerbations, and antibiotic use were adjusted for the effect of elexacaftor/tezacaftor/ivacaftor treatment. RESULTS: One hundred twenty-four patients participated. One hundred ten patients were analyzed (mean age, 35 years; range, 18-69 years). Ninety-five percent had access to telemedicine (n = 105). Telemedicine visits accounted for 64% of encounters (n = 260), hybrid visits with telemedicine support accounted for 28% of encounters (n = 114), and in-person visits accounted for 7% of encounters (n = 30). No difference in lung function or exacerbation rate during the PY was found. BMI increased from 25 to 26 kg/m2 (t100 = -4.72; P < .001). Antibiotic use decreased from 316 to 124 episodes (z = 8.81; P < .0001). INTERPRETATION: This CF care model, which includes IDC-TM, successfully monitored lung function and BMI, identified exacerbations, and followed guidelines-based care during the pandemic. A significant decrease in antibiotic use suggests that social mitigation strategies were protective. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04402801; URL: www. CLINICALTRIALS: gov.


Subject(s)
COVID-19 , Cystic Fibrosis , Telemedicine , Adult , Anti-Bacterial Agents/therapeutic use , COVID-19/epidemiology , Cystic Fibrosis/drug therapy , Cystic Fibrosis/therapy , Humans , Pandemics , Retrospective Studies
11.
Am J Cancer Res ; 11(10): 4768-4787, 2021.
Article in English | MEDLINE | ID: mdl-34765292

ABSTRACT

Triple-Negative Breast Cancers (TNBCs) constitute roughly 10-20% of breast cancers and are associated with poor clinical outcomes. Previous work from our laboratory and others has determined that the cytoplasmic adaptor protein Breast Cancer Antiestrogen Resistance 3 (BCAR3) is an important promoter of cell motility and invasion of breast cancer cells. In this study, we use both in vivo and in vitro approaches to extend our understanding of BCAR3 function in TNBC. We show that BCAR3 is upregulated in ductal carcinoma in situ (DCIS) and invasive carcinomas compared to normal mammary tissue, and that survival of TNBC patients whose tumors contained elevated BCAR3 mRNA is reduced relative to individuals whose tumors had less BCAR3 mRNA. Using mouse orthotopic tumor models, we further show that BCAR3 is required for efficient TNBC tumor growth. Analysis of publicly available RNA expression databases revealed that MET receptor signaling is strongly correlated with BCAR3 mRNA expression. A functional role for BCAR3-MET coupling is supported by data showing that both proteins participate in a single pathway to control proliferation and migration of TNBC cells. Interestingly, the mechanism through which this functional interaction operates appears to differ in different genetic backgrounds of TNBC, stemming in one case from potential differences in the strength of downstream signaling by the MET receptor and in another from BCAR3-dependent activation of an autocrine loop involving the production of HGF mRNA. Together, these data open the possibility for new approaches to personalized therapy for individuals with TNBCs.

12.
PLoS One ; 16(8): e0256388, 2021.
Article in English | MEDLINE | ID: mdl-34415938

ABSTRACT

The maned wolf (Chrysocyon brachyurus) is an induced ovulator. Though the mechanism of ovulation induction remains unknown, it is suspected to be urinary chemical signals excreted by males. This study assessed volatile organic compounds (VOCs) in weekly urine samples across 5 months from 13 maned wolves (6 intact males, 1 neutered male, 6 females) with the goal of identifying VOCs that are differentially expressed across sex, reproductive status, and pairing status. Solid-phase microextraction (SPME) and gas chromatography-mass spectrometry (GC-MS) were used to extract and separate VOCs that were identified via spectral matching with authentic standards, with spectral libraries, or with new software that further matches molecular fragment structures with mass spectral peaks. Two VOCs were present across all 317 urine samples: 2,5-dimethyl pyrazine and 2-methyl-6-(1-propenyl)-pyrazine. Fifteen VOCs differed significantly (Adj. P < 0.001 and |log2 fold change| >2.0) between intact males and females. Using partial least squares-discriminant analysis, the compounds with the highest importance to the sex classification were delta-decalactone, delta-dodecalactone, and bis(prenyl) sulfide. Sixty-two VOCs differed between intact males and the neutered male. Important classifier compounds were 3-ethyl 2,5-dimethyl pyrazine, 2-methyl-6-(1-propenyl)-pyrazine, and tetrahydro-2-isopentyl-5-propyl furan. Several VOCs established as important here have been implicated in reproductive communication in other mammals. This study is the most robust examination of differential expression in the maned wolf thus far and provides the most comprehensive analysis of maned wolf urinary VOCs to date, increasing the sample size substantially over previous chemical communication studies in this species. New data analysis software allowed for the identification of compounds in the hormone-producing mevalonate pathway which were previously unreported in maned wolf urine. Several putative semiochemicals were identified as good candidates for behavioral bioassays to determine their role in maned wolf reproduction, and specifically in ovulation induction.


Subject(s)
Canidae , Animals , Reproduction , Volatile Organic Compounds
13.
Cancer Med ; 9(18): 6533-6549, 2020 09.
Article in English | MEDLINE | ID: mdl-32710512

ABSTRACT

Large granular lymphocyte (LGL) leukemia is a rare hematological disorder with expansion of the T-cell or natural killer (NK) cell lineage. Signal transducer and activator of transcription 3 (STAT3) exhibits somatic activating mutations in 30%-40% of LGL leukemia cases. Transcriptional targets of STAT3 include inflammatory cytokines, thus previous studies have measured cytokine levels of LGL leukemia patients compared to normal donors. Sphingolipid metabolism is a growing area of cancer research, with efforts focused on drug discovery. To date, no studies have examined serum sphingolipids in LGL leukemia patients, and only one study compared a subset of cytokines between the T-LGL and NK-LGL subtypes. Therefore, here, we included both LGL leukemia subtypes with the goals of (a) measuring serum sphingolipids for the first time, (b) measuring cytokines to find distinctions between the subtypes, and (c) establishing relationships with STAT3 mutations and clinical data. The serum analyses identified cytokines (EGF, IP-10, G-CSF) and sphingolipids (SMC22, SMC24, SMC20, LysoSM) significantly different in the LGL leukemia group compared to normal donors. In a mixed STAT3 mutation group, D661Y samples exhibited the highest mean corpuscular volume (MCV) values. We explored this further by expanding the cohort to include larger groups of single STAT3 mutations. Male D661Y STAT3 samples had lower Hgb and higher MCV compared to wild type (WT) or Y640F counterparts. This is the first report examining large groups of individual STAT3 mutations. Overall, our results revealed novel serum biomarkers and evidence that D661Y mutation may show different clinical manifestation compared to WT or Y640F STAT3.


Subject(s)
Cytokines/blood , Leukemia, Large Granular Lymphocytic/blood , Leukemia, Large Granular Lymphocytic/genetics , Mutation , STAT3 Transcription Factor/genetics , Sphingolipids/blood , Adult , Aged , Aged, 80 and over , Biomarkers/blood , Case-Control Studies , Female , Humans , Leukemia, Large Granular Lymphocytic/diagnosis , Male , Middle Aged , Registries , Young Adult
14.
Sci Rep ; 10(1): 619, 2020 Jan 14.
Article in English | MEDLINE | ID: mdl-31932665

ABSTRACT

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

15.
Sci Rep ; 9(1): 15709, 2019 10 31.
Article in English | MEDLINE | ID: mdl-31673099

ABSTRACT

Identifying genetic variants that regulate binge eating (BE) is critical for understanding the factors that control this behavior and for the development of pharmacological treatment strategies. Although several studies have revealed specific genes capable of affecting BE behavior, less is known about how genetic variation modulates BE. Thus, through a paradigm that promoted binge-like food intake through intermittent access to high calorie diet (HCD), we quantified food-intake in four inbred mouse strains: C57Bl/6J (B6), NOD/LtJ (NOD), 129S1/SvlmJ (S1), and A/J (AJ). We report that genetic variation likely influences the chronic regulation of food intake and the binge-like consumption of a palatable HCD. AJ mice consumed more of both standard chow and HCD than the other three strains tested when both diets were available ad libitum, while S1 mice consumed significantly less HCD than other strains during intermittent HCD access. Behavioral differences were also associated with differential changes in c-Fos immunohistochemistry in brain regions traditionally associated with appetite regulation. Our results identify 129S1/SvlmJ as a strain that exhibits low levels of binge feeding behavior and suggests that this strain could be useful in the investigation of the influence of genetic variation in the control of binge food intake.


Subject(s)
Feeding Behavior , Genetic Variation , Animals , Binge-Eating Disorder/genetics , Disease Models, Animal , Female , Mice , Mice, Inbred Strains
16.
JCI Insight ; 52019 04 02.
Article in English | MEDLINE | ID: mdl-30939126

ABSTRACT

The prefrontal cortex controls food reward seeking and ingestion, playing important roles in directing attention, regulating motivation towards reward pursuit, and the assignment of reward salience and value. The cell types that mediate these behavioral functions, however, are not well described. We report here that optogenetic activation of vasoactive peptide expressing (VIP) interneurons in both the infralimbic (IL) and prelimbic (PL) divisions of the medial prefrontal cortex in mice is sufficient to reduce acute, binge-like intake of high calorie palatable food in the absence of any effect on low calorie rodent chow intake in the sated animal. In addition, we discovered that the behavioral mechanisms associated with these changes in feeding differed between animals that underwent either IL or PL VIPergic stimulation. While IL VIP neurons showed the ability to reduce palatable food intake, this effect was dependent upon the novelty and relative value of the food source. In addition, IL VIP neuron activation significantly reduced novel object- and novel social investigative behavior. Activation of PL VIP neurons, however, produced a reduction in high calorie palatable food intake that was independent of food novelty. Neither IL nor PL VIP excitation changed motivation to obtain food reward. Our data show how neurochemically-defined populations of cortical interneurons can regulate specific aspects of food reward-driven behavior, resulting in a selective reduction in intake of highly valued food.


Subject(s)
Eating/psychology , Neurons/physiology , Optogenetics , Prefrontal Cortex/physiology , Vasoactive Intestinal Peptide/metabolism , Animals , Behavior, Animal/physiology , Cognition , Food , Homeostasis , Male , Mice , Mice, Inbred C57BL , Obesity , Reward
17.
Gen Comp Endocrinol ; 267: 109-115, 2018 10 01.
Article in English | MEDLINE | ID: mdl-29913172

ABSTRACT

The maned wolf is a threatened canid species native to South America. Previous studies have suggested the species exhibits induced ovulation. In captive breeding facilities, reproductive success is low while rates of neonatal mortality are high. Females that are not recommended for breeding are frequently housed together. However there has never been a systematic study of the reproductive consequences of co-housing females. This study was conducted for three purposes, to: (1) corroborate the presence of induced ovulation, (2) determine whether elevated cortisol is implicated in neonatal pup mortality, and (3) evaluate the endocrine correlates of group housed females. Using fecal hormone monitoring for estrogen, progesterone, and cortisol, 43 cycles from 33 female maned wolves were studied from 2002 to 2015. Females were categorized by their reproductive status: pregnant and successfully raised pups (PR; n = 11), pregnant with neonatal pup demise within 3 days (PL; n = 7), housed with a male but no signs of breeding or pregnancy (PP; n = 10), housed singly (S; n = 8), or housed with related females (F; n = 7). Estrogen and progestagen remained at baseline for all females not housed with a male (S, F), while elevations consistent with ovulation were seen in females housed with a male (PP, PL, PR). Compared to PR females, PL individuals showed similar cortisol levels throughout the cycle and slightly lower progesterone levels during gestation. As for the effect of co-housing related females, F females showed estrogen and progesterone levels lower even than S females while cortisol levels were elevated compared to all other groups. These findings support the previous evidence of induced ovulation in the maned wolf. Although elevated cortisol does not seem to be implicated in pup loss, a non-significant trend towards lower progesterone during gestation could be implicated. Future studies should assess depressed progesterone levels as a correlate to neonatal pup mortality. Female maned wolves housed with related females experience suppressed reproductive hormones and elevated adrenal hormones. Therefore, a more systematic study of hormonal and behavioral correlates to co-housing with related females is warranted.


Subject(s)
Canidae/physiology , Housing, Animal , Animals , Estrogens/metabolism , Feces/chemistry , Female , Hydrocortisone/metabolism , Male , Metabolome , Pregnancy , Progesterone/metabolism , Progestins/metabolism , Reproduction/physiology , South America
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